GENOME RESEARCH CENTRE
| Researcher : Leung TY |
| List of Research Outputs |
| Lung S.C., Leung A.S.P., Kuang R., Wang Y., Leung T.Y. and Lim B.L., The phytase secreted by tobacco (Nicotiana tabacum) into root exudates is a purple acid phosphatase. , Phytochemistry. 2008, 69: 365-373. |
| Researcher : Mak WW |
| List of Research Outputs |
| Sabeti P.C., Varilly P., Fry B., Lohmueller J., The International HapMap Consortium -., Tsui L.C., Mak W.W., Song Y. and Tam P.K.H., Genome-wide detection and characterization of positive selection in human populations (Co-PI of Hong Kong Centre which responsible 2.5% of genome), Nature. 2007, 449(7164): 913-918. |
| The International HapMap Consortium -., Tsui L.C., Mak W.W., Song Y. and Tam P.K.H., A second generation human haplotype map of over 3.1 million SNPs (Co-PI of Hong Kong Centre which responsible 2.5% of genome), Nature. 2007, 449(7164): 851-861. |
| Researcher : Song Y |
| Project Title: | Genetic linkage analysis of early onset degenerative disc disease in Southern Chinese |
| Investigator(s): | Song Y, Cheah KSE, Cheung KMC, Leong JCY, Chan D |
| Department: | Biochemistry |
| Source(s) of Funding: | Competitive Earmarked Research Grants (CERG) |
| Start Date: | 11/2003 |
| Abstract: |
| To detect linkage associated with early onset familial DDD by performing a genome-wide scan; to define the chromosomal location of the early onset familial DDD gene; to begin preliminary work towards positional/candidate clonning. |
| Project Title: | Mapping and cloning a new gene on chromosome 8q24 for amyotrophic lateral sclerosis in a large Chinese family |
| Investigator(s): | Song Y, Ho SL, Fong CY |
| Department: | Biochemistry |
| Source(s) of Funding: | Competitive Earmarked Research Grants (CERG) |
| Start Date: | 01/2005 |
| Abstract: |
| Biomarkers detection; detection possible ALS modifier on chromosome 10 in Branch A; longitudinal follow-up of both branches; mapping the CMT II locus in Branch B. |
| Project Title: | Mapping a genetic modifier for heart defects in Type IIA procollagen deficient mutant mice |
| Investigator(s): | Song Y |
| Department: | Genome Research Centre |
| Source(s) of Funding: | Competitive Earmarked Research Grants (CERG) |
| Start Date: | 01/2006 |
| Abstract: |
| To perform a genome-wide scan using mouse microsatellite markers to map the modifer locus to within a 20cM region; to generate region-specific speed modifer congenic mice for fine mapping of this 20cM region; to map the modifier locus to a 1cM region and combine with the results of gene expression in the modifier region to provide the essential genetic resources for future studies aimed at precise identification of the modifier gene. |
| List of Research Outputs |
| Cheung K.M.C., Song Y., Ho D.W.H., Poon S.C.S., Chiba K., Kawaguchi Y., Hirose Y., Alini M., Grad S., Yee A.F.Y., Leong J.C.Y., Luk K.D.K., Yip S.P., Karppinen J., Cheah K.S.E., Sham P.C., Ikegawa S. and Chan D., Association of the asporin D14 allele with lumbar disc degeneration, Spineweek 2008, Geneva, Switzerland, May 26-31, 2008. |
| Kao P.Y.P., Chan D., Cheung K.M.C., Ho D.W.H., Karppinen J., Leong J.C.Y., Luk K.D.K., Yip S.P., Cheah K.S.E., Song Y., Sham P.C. and Sham P.C., Genome-wide association study of degenerative disc disease, Spineweek 2008, Geneva, Switzerland, May 26-31, 2008. |
| Sabeti P.C., Varilly P., Fry B., Lohmueller J., The International HapMap Consortium -., Tsui L.C., Mak W.W., Song Y. and Tam P.K.H., Genome-wide detection and characterization of positive selection in human populations (Co-PI of Hong Kong Centre which responsible 2.5% of genome), Nature. 2007, 449(7164): 913-918. |
| Song Y., Ho D.W.H., Karppinen J., Kao P.Y.P., Fan B.J., Luk K.D.K., Yip S.P., Leong J.C.Y., Cheah K.S.E., Sham P.C., Chan D. and Cheung K.M.C., Association between promoter-1607 polymorphism of MMP1 and lumbar disc disease in Southern Chinese, BMC Medical Genetics. 2008, 9(1): 38. |
| Song Y., Cheung K.M.C., Ho D.W.H., Poon S.C.S., Chiba K., Kawaguchi Y., Hirose Y., Alini M., Grad S., Yee A.F.Y., Leong J.C.Y., Luk K.D.K., Yip S.P., Karppinen J., Cheah K.S.E., Sham P.C., Ikegawa S. and Chan D., Association of the asporin D14 allele with lumbar disc degeneration in Asians, American Journal of Human Genetics. 2008, 82(3): 744-747. |
| The International HapMap Consortium -., Tsui L.C., Mak W.W., Song Y. and Tam P.K.H., A second generation human haplotype map of over 3.1 million SNPs (Co-PI of Hong Kong Centre which responsible 2.5% of genome), Nature. 2007, 449(7164): 851-861. |
| Researcher : Wang Y |
| Project Title: | The Fat-Derived Hormone Adiponectin as a Potential Factor Linking Obesity and Breast Cancer |
| Investigator(s): | Wang Y, Xu A |
| Department: | Genome Research Centre |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 06/2006 |
| Abstract: |
| 1. Background and Research hypothesis: Obesity and its related diseases are now reaching an epidemic level and form one of the major burdens for our current healthcare system worldwide [1]. Recent epidemiological studies suggested that an increase in the risk of cancer is one of the consequences of obesity. The predominant cancers associated with obesity are lifestyle-related and have a hormonal base including breast, prostate, endometrium, colon and gallbladder cancers etc. [2]. Although the exact mechanism of this relationship remains to be determined, many evidence indicated that excess formation of adipose tissue surrounding the malignant cells might play important roles in tumor-microenvironment interaction and in controlling local cancer growth, invasion and distant metastasis [3]. Adipose tissue was traditionally considered to be an inert energy storage organ. However, recent evidences suggested that adipocytes (fat cells) can also produce a variety of biologically active polypeptides, hormones, growth factors and cytokines, collectively called adipokines [4]. Adipokines elicit their diversified actions on angiogenesis, inflammation, lipid/glucose metabolism, haemostasis, immunity and stress-response etc in an endocrine, paracrine and autocrine manner [5]. It is now generally accepted that endocrine dysfunction of adipose tissue may represent one of the causal links between obesity and systemic insulin resistance/diabetes. Interestingly, diabetes and hyperglycemia are also associated with an elevated risk of developing pancreatic, liver, colon, breast, and endometrial cancer [6], suggesting that the dysregulated secretion of adipokines might represent a general mechanism linking obesity and cancer formation. Indeed, many adipokines, such as leptin, tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6), not only causatively link to metabolic diseases but also play important roles in carcinogenesis. In addition, various growth factors/hormones produced from adipocytes in the local tumor environment might act directly on carcinoma cells to stimulate tumor growth and angiogenesis [7,8]. Breast cancer is the most frequent cancer in women and represents the second leading cause of cancer death among women [9]. Obesity is an independent risk factor for the development of breast cancer and is associated with late-stage disease and poor prognosis [10]. Post-menopausal women with upper body fat predominance have a higher risk of breast cancer [11]. The past several years have provided substantial evidence for the vital roles of stromal cells on the tumorigenesis of the mammary ductal epithelial cells [3]. Stromal cells can influence the level of invasiveness and malignancy of the tumor by producing various matrix metalloproteases (MMPs) and growth/angiogenesis stimulators including IGF, VEGF, HGF, FGF and TGF etc. Notably, adipocyte (fat cell) is one of the predominant stromal cell types in the microenvironment of mammary tissue and the proximity suggests that adipocytes could be a key player in the stromal-ductal epithelium interactions. Indeed, the close relationship between adipocytes and mammary tumor growth has been demonstrated by many in vitro and in vivo pharmacological studies [3]. Aromatase in adipose tissue stroma provides an important source of estrogen for the postmenopausal woman. Mature adipocytes can promote the growth of breast carcinoma cells in a collagen gel matrix culture through cancer-stromal cell interactions [12]. Co-transplantation of tumor cells with adipocytes into mice results in increased tumor growth and metastasis [13]. Leptin, a hormone mainly produced in adipose tissue, could act as a paracrine/endocrine growth factor towards mammary epithelial cells and contribute to the development of breast cancer [14,15]. A recent report by Iyengar P. et al suggested that collagen VI secreted from adipocytes could affect early mammary tumor progression and might represent one of the adipokines that have pro-tumorigenic functions [16]. In summary, these evidences suggest that adipose tissue-derived factors might significantly influence the growth and proliferation of tumorous stroma and malignant cells in the local environment of mammary tissue. Adiponectin is a circulating hormone exclusively secreted from adipocytes. Unlike many other adipokines, such as TNFα, IL-6, leptin, heparin-binding epidermal growth factor-like growth factor, hepatocyte growth factor and resistin etc that are increased in obesity, the circulating levels of adiponectin are inversely correlated with obesity and insulin resistance, two risk factors of breast cancer [10]. Adiponectin has been demonstrated to have insulin-sensitizing, anti-inflammatory, anti-diabetic and anti-atherogenic activities whereas most other adipokines are causatively linked to obesity-related diseases [17]. Replenishment of adiponectin in animal models can reduce the body weight, improve glucose/lipid homeostasis, increase insulin sensitivity, prevent atherosclerosis and ameliorate fatty liver diseases. In addition, adiponectin possesses anti-angiogenic and anti-tumor activities as demonstrated by its ability to inhibit cell growth and migration of vascular endothelial cells, prevent new blood vessel formation, and attenuate the growth of transplanted fibrosarcoma cell tumors in mice [18]. Although the detailed relationship between adiponectin expression in local mammary tissue and the development of breast cancer have not been fully established, recent clinical studies have shown that obese women have reduced serum adiponectin levels and low serum adiponectin levels are significantly associated with an increased risk for breast cancer [10,19-22]. Moreover, tumours in women with the low serum adiponectin levels are more likely to show a biologically aggressive phenotype [22]. Notably, we and others have shown that adiponectin has inhibitory activities on the proliferation of a variety of different types of cells, including aortic smooth muscle cells, myelomonocytic cells, endothelial cells and hepatic stellate cells etc [23-27]. It can selectively bind to various carcinogenic growth factor and prevent the interactions of these growth factors to their respective receptors [24]. In line with these clinical findings, our preliminary studies revealed that recombinant adiponectin could significantly attenuate the cell growth of an estrogen receptor (ER)-negative breast cancer cell line, MDA-MB-231, in a time-dependent manner. It could also inhibit the proliferation stimulated by insulin and several other growth factors in an ER-positive breast cancer cell line, T47D. Moreover, our results from DNA fragmentation assay suggest that apoptosis was significantly induced in MDA-MB-231 cells after 48 hours treatment with adiponectin. Based on aforementioned clinical and experimental evidences, we hypothesize that adiponectin might be a negative regulator in breast cancer development, and that replenishment of this protein might represent a novel therapeutic strategy for the treatment of obesity-related breast cancer. 2. Specific objectives: (1). To test whether adiponectin has inhibitory roles on the migration/invasion of breast carcinoma cells and the angiogenesis stimulated by these cells. (2). To investigate the potential mechanism that underlies the growth-inhibitory effects of adiponectin in breast cancer cells. (3). To evaluate the effects of adiponectin on tumor growth/metastasis in athymic nude mice inoculated with breast cancer cells using adenovirus-mediated overexpression system. |
| Project Title: | Role of Mitochondria in Adiponectin-mediated Protective Effects Against Obesity-related Hepatic Steatosis and Steatohepatitis |
| Investigator(s): | Wang Y, Xu A |
| Department: | Genome Research Centre |
| Source(s) of Funding: | Seed Funding Programme for Basic Research |
| Start Date: | 07/2007 |
| Abstract: |
| Non-alcoholic fatty liver disease (NAFLD) is one of the major health concerns closely associated with obesity, which is now reaching an epidemic level worldwide [1]. Recent studies suggest that NAFLD is also the component of the metabolic syndrome, a constellation of several inter-related risk factors for Type 2 Diabetes and cardiovascular diseases [2]. NAFLD is the most frequent hepatic lesion in developed countries, with an estimated prevalence of 10-25% [3]. The presence of steatosis in liver is an important risk factor for the development of additional liver injuries, such as non-alcoholic steatohepatitis (NASH), viral hepatitis, drug-induced hepatotoxicity and alcoholic steatohepatitis (ASH) etc [4]. About 5 % of hepatic steatosis will progress to significant fibrosis and cirrhosis and over 80 % of these cases will further develop liver cancer [1]. Adiponectin is an important adipokine abundantly produced from adipose tissues [5]. This adipokine has recently attracted great attention due to its anti-diabetic and anti-atherogenic activitities [6]. Circulating concentrations of adiponectin are decreased in obesity and its related pathologies, including insulin resisatnce, type 2 diabetes and cardiovascular diseases [6]. Supplementation with recombinant adiponectin could improve insulin sensitivity, decrease blood glucose levels, reverse atherogenic dyslipidemia and alleviate atherosclerosis in various animal models [5]. A previous study from our group provided the first evidence demonstrating that adiponectin possesses potent protective effects against both alcoholic and nonalcoholic fatty liver disease and steatohepatitis [7]. In both ethanol-fed mice and ob/ob obese mice, chronic treatment with recombinant adiponectin markedly attenuated hepatomegaly and steatosis, and also significantly decreased the hepatic inflammation loci and serum alanine aminotransferase (ALT), an established marker of liver injury [7]. More recently, we demonstrated that adiponectin treatment could also attenaute liver injury and fibrosis induced by pharmacological compounds and bile duct ligations [8]. Consistent with our data, several other group has recently confirmed the hepato-protective effects in different animal models with liver injury, such as carbon tetrachloride-treated mice with fibrosis and lipopolysaccharide (LPS)/D-galactosamine-treated mice with steatosis and inflammation [9-11]. These animal data were also supported by our clinical observations showing an inverse association between serum levels of adiponectin and ALT in Chinese obese subjects [7]. Moreover, plasma adiponectin levels are significantly lower in patients with NAFLD compared to the sex and age matched healthy controls [12, 13]. NASH patients with lower levels of adiponectin show higher grades of inflammation [14]. In addition, decreased plasma adiponectin concentrations are closely related to steatosis in hepatitis C virus-infected patients [15]. Taken together, these clinical and animal data suggest that low plasma levels of adiponectin might be an important risk factor for the development of fatty liver, steatohepatatis and other forms of liver injury. Adiponectin and its agonists might represent an effective strategy for treatment and prevention of these diseases. Nevertheless, the molecular and cellular mechanisms underlying the hepato-protective effects of adiponectin remain largely elusive so far. It is now known that mitochondrial dysfunction plays a central role in various forms of hepatic steatosis and liver injury [16-18]. Mitochondria are involved in fatty acid β-oxidation, tricarboxylic acid cycle (TCA) and oxidative phosphorylation. In patients with NASH, the hepatic mitochondria exhibit ultrastructural lesions and decreased activity of respiratory chain complexes [19, 20]. In this condition, the decreased activity of the respiratory chain results in accumulation of reactive oxygen species (ROS), and oxidization of fat deposits to form lipid peroxidation products, which in turn , may cause the diverse lesions of steatohepatitis, necrosis, inflammation, and fibrosis [21, 22]. The increased mitochondrial ROS formation in steatohepatitis could directly damage mitochondria DNA (mtDNA) and respiratory chain polypeptides, which further block the flow of electrons within the respiratory chain [20, 23]. Moreover, ROS cause NF-κB activation and induce the hepatic synthesis of tumor necrosis factor-α (TNF α), which triggers mitochondria membrane permeability and apoptosis [24]. Impaired mitochondrial integrity and transcriptional capacity have also been observed in LPS- and retrovirus-mediated hepatic injury [25, 26]. Taken together, these evidences suggest that mitochondria dysfunction might play a key role in the pathogenesis of NAFLD, NASH and other forms of liver injuries. In this study, we will test our hypothesis that adiponectin exerts its hepato-protective effects partly through promoting mitochondrial biogenesis and allevaiting mitochondria dysfunctions. The specific objectives are: 1. To investigate whether the accelerated liver injury is associated with impaired mitochondria dysfunction in adiponectin knockout mice; 2. To test whether adenovirus-mediated overexpression of adiponectin stimulates mitochondria biogenesis and reverses mitochondria dysfunction associated with obese mice. 3. To elucidate the potential signalling pathways involved in adiponectin-mediated modulation of mitochondria functions in liver. |
| List of Research Outputs |
| Lithander F., Keogh G., Wang Y., Cooper G. and Poppit S., No Evidence of an Effect of Alterations in Dietary Fatty Acids on Fasting Adiponectin Over 3 Weeks, Obesity. 2008. |
| Lithander F.E., Keogh G.F., Wang Y., Cooper G.J. and Poppitt S.D., No evidence of an effect of alterations in dietary Fatty acids on fasting adiponectin over 3 weeks. . 2008, 16: 592-9. |
| Liu L., Wang Y., Lam K.S.L. and Xu A., Moderate wine consumption in the prevention of metabolic syndrome and its related medical complications, Endocr Metab Immune Disord Drug Targets (Invited review). 2008, 8: 89-98. |
| Lung S.C., Leung A.S.P., Kuang R., Wang Y., Leung T.Y. and Lim B.L., The phytase secreted by tobacco (Nicotiana tabacum) into root exudates is a purple acid phosphatase. , Phytochemistry. 2008, 69: 365-373. |
| Palanivel R., Eguchi M., Liu Y., Wang Y., Xu A. and Sweeney G., Globular and full-length forms of adiponectin mediate specific changes in glucose and fatty acid uptake and metabolism in cardiomyocytes. , Cardiovasc Res. . 2007, 75: 148-57. |
| Palanivel R., Fang X., Park M., Eguchi M., Pallan S., De Girolamo S., Liu Y., Wang Y., Xu A. and Sweeney G., Globular and full-length forms of adiponectin mediate specific changes in glucose and fatty acid uptake and metabolism in cardiomyocytes., Cardiovascular Research. 2007, 75: 148-57. |
| Seneviratne C.J., Wang Y., Jin L.J., Abiko Y. and Samaranayake L.P., Candida albicans biofilm formation is associated with increased anti-oxidative capacities, Proteomics. 2008, 8(14): 2936-47. |
| Tso A.W.K., Xu A., Sham P.C., Wat N.M.S., Wang Y., Fong C.H., Cheung B.M.Y., Janus E.D. and Lam K.S.L., Serum adipocyte fatty acid binding protein as a new biomarker predicting the development of type 2 diabetes: a 10-year prospective study in a Chinese cohort, Diabetes Care. 2007, 30: 2667-72. |
| Wang Y., Fong P.Y., Leung F.C.C., Mak W. and Sham P.C., Increased gene coverage and Alu frequency in large linkage disequilibrium blocks of the human genome, Genetics and Molecular Research. 2007, 6: 1131-1141. |
| Researcher : Xu R |
| Project Title: | Oral gene therapy of tumors by using recombinant AAV-TRAIL viral vectors |
| Investigator(s): | Xu R, Kung H |
| Department: | Institute of Molecular Biology |
| Source(s) of Funding: | Matching Fund for Hi-Tech Research and Development Program of China (863 Projects) |
| Start Date: | 05/2002 |
| Abstract: |
| To study tumor therapy by using recombinant AAV. |
| Project Title: | Peroral transduction of hepatocytes for diabetes gene therapy |
| Investigator(s): | Xu R, Lam KSL |
| Department: | Institute of Molecular Biology |
| Source(s) of Funding: | Competitive Earmarked Research Grants (CERG) |
| Start Date: | 10/2002 |
| Abstract: |
| A major goal of gene therapy for Diabetes Mellitus (DM) is to restore long-term euglycemia. This study shall focus on clarifying the adeno-associated virus (AAV) vector transportation pathway from stomach to liver after oral administration. The research team will extend their previous study further to develop chimeric glucose- and insulin-sensitive promoters and insert them into the existing AAV vector system. |
| Project Title: | Preclinical study of lung cancer therapy using recombinant adeno-associate virus vector |
| Investigator(s): | Xu R |
| Department: | Institute of Molecular Biology |
| Source(s) of Funding: | Matching Fund for Hi-Tech Research and Development Program of China (863 Projects) |
| Start Date: | 04/2003 |
| Abstract: |
| To carrry out preclinical study of lung cancer therapy using recombinant adeno-associate virus vector. |
| List of Research Outputs |
| Li H., Li X., Lam K.S.L., Tam S., Xiao W. and Xu R., Adeno-associated virus-mediated pancreatic and duodenal homeobox gene-1 expression enhanced differentiation of hepatic oval stem cells to insulin-producing cells in diabetic rats, J Biomed Sci.. 2008, Epub ahead of print. |